Schizophrenia (SZ) is thought to be a disorder due in part to abnormal connectivity within and between brain regions. The symptoms present in schizophrenia are not only related to abnormalities in specific brain regions and neurotransmitters, but also are related to aberrant communication within and between networks of brain regions that are structurally connected by fiber pathways. This abnormal connectivity within and between brain regions in SZ is termed dysconnectivity. Abnormalities in structural or functional connectivity or the coupling of the two could be due to disorders of the white matter, ie the axon bundles connecting distant regions of the brain. Imaging studies have shown abnormalities in white matter in the brains of subjects with SZ. Studies conducted with postmortem tissue, where higher resolution studies can be performed, show different types of pathology. In this proposal we intend to examine major white matter tracts that connect areas of the brain that are abnormal is SZ, including the internal capsule, cingulum bundle, and corpus callosum. We hypothesize that there will be abnormalities in white matter integrity in SZ that could underlie abnormal connectivity, including anomalies in myelin, glia, mitochondria, and/or the cytoskeleton. We will approach this hypothesis using protein studies, histology, immunohistochemistry and electron microscopy in postmortem tissue from SZ subjects on or off APD and a matched comparison group to determine which deficits could result in impaired network activity. SA1) Using western blots we will measure proteins including: myelin basic protein, markers of oligodendrocytes, microtubule associated protein, neurofilament, and markers of mitochondrial function. SA2) will use histology and immunocytochemistry to confirm and further localize changes identified in SA1). SA3) Using electron microscopy (EM), we will count and measure the cross sectional area of axons and myelin sheaths and measure the structural integrity of glial cells. Here we propose a low risk, high throughput study to identify the underpinnings of structural dysconnectivity in major white matter pathways in postmortem SZ brain. The study is novel, as it will combine different techniques and study several white matter tracks in the same brains. In addition, we will use electron microscopy, a rarely used technique in postmortem human brain, to answer questions that can only be answered with electron microscopy. The results of these studies will allow us to more comprehensively understand the white matter pathology in schizophrenia, and hopefully to identify targets for new treatment mechanisms.